The functioning of the central nervous system (CNS), including the brain, is highly dependent on a variety of receptor sites which show more or less specific binding capacity for a variety of natural (endogenous) chemical entities. The actions of some drugs (foreign chemical substances) relate to their capacity to bind to such specific receptors, thus either triggering or blocking the actions influenced by the receptors. The existence of some brain receptors first came to be detected by the discovery that certain active drugs bind to them. Consequently, such receptors may be named after the drug involved, for example, morphine receptors or benzodiazepine receptors. The scientist then seeks to learn the nature of the endogenous (natural) substance in the brain which react with these receptors to better understand the normal function of the receptor, and its role in disease and the action of relevant drugs.
Thus, benzodiazepiine receptors are naturally occurring binding sites found within the CNS generally in all animals, including man. These receptors directly influence an animal's behavioral characteristics. They are called benzodiazepine receptors because one broad class of pharmacologically active compounds able to bind to them, are collectively of the chemical structure known as benzodiazepines. Agents which bind to these receptors are able to directly influence, modify or control in varying degrees the neurological and behavioral patterns of mammals.
The benzodiazepines and benzodiazepine-like compositions are often used as drugs for a wide variety of neuropsychiatric conditions of man, but their most popular use is in the treatment of anxiety. The full range of pharmacological effects caused by the binding of these pharmacologically active compositions to the benzodiazepine receptors in the central nervous system includes anticonvulsant, muscle relaxant, anxiolytic and sedative properties, and the effect in animals can be correlated directly with such activity in man. For more specific details, see Tallman, Paul, Skolnick and Gallager, Science, 207:274 (1980); Greenblatt and Schder, Benzodiazepine in Clinical Practice, (1974); Garattine, Mussiri and Randall, The Benzodiazepines (1973); and Zoinden and Randall, Advanced Pharmacology, 5:213 (1967).
According to a recent conservative estimate, at least 8,000 tons of benzodiazepines are consumed each year in the United States alone. This estimate, however, is based only upon the consumption of chlordiazepoxide (Librium), diazepam (Valium) and flurazepam (Dalmane). The widespread use and abuse, intentionally or accidentally, of benzodiazepines and benzodiazepine-like drugs with their concomitant risk of seizures and other adverse reactions due to excessive dosage or withdrawal reactions, have drawn attention to the need for and importance of identifying the natural biochemically and pharmacologically active ligands which may be modulators and able to influence the receptor involved in the action of the benzodiazepine.
Until recently, little was known about the identity of the endogenous (natural) ligand(s) which interact with the so-called benzodiazepine receptor. Generally, the therapeutic use of an endogenous ligand normally found in the central nervous system which influences a given receptor is preferred to a foreign synthetic chemical. Such naturally occurring agents are less likely to cause drug-induced side effects, either by direct action or as a result of withdrawal.
Some studies have suggested that the purine nucleosides inosine, 2-deoxyinosine and 2-deoxyguanosine may act as endogenous ligands and, therefore, as modulators of the benzodiazepine receptors in the central nervous system (See Life Science, 24:851 (1979); Science, p. 727 (1981); Proc. Natl. Acad. Sci., 74:3805 (1977); and Science, 198:849 (1977). Inosine, in particular, is recognized as a benzodiazepine antagonist: it is able to antogonize the gamma aminobutyric acidmimetic action of diazepam in vivo, antagonize pentylenetetrazole-induced seizures, and reverse diazepam-induced stimulation of mouse exploratory behavior (See Life Science, 25:1963 (1979); and Proc. Natl. Acad., 76:1515 (1979). A major difficulty, however, is that inosine in vivo is a substrate for the enzyme purine nucleoside phosphorylase (PNP) which also is found normally in brain tissue. Increased concentrations of inosine are difficult to achieve because of the action of this enzyme within the CNS. Consequently, the utility of inosine itself as a therapeutic agent is very limited, even if it did reach the brain. The other purine nucleosides are similarly limited in various respects unless PNP is blocked.
Accordingly, insofar as is presently known, no endogenous modulating ligand has been isolated which can be maintained in the CNS in sufficiently high concentration to serve as a substitute for or modulator of benzodiazepine and benzodiazepine-like composition to reduce or entirely prevent the severity and frequency of seizures, whether induced by drugs, indigenously or by other factors.